Cis-azole derivatives, intermediates thereof and fungicidal compositions

ABSTRACT

Disclosed herein is a process for preparing a cis-azole derivative represented by the general formula (I) ##STR1## wherein R 1  and R 2  denote each a hydrogen atom or an alkyl group, R denotes a halogen atom, a nitro group, a cyano group, an alkyl group, a haloalkyl group or a phenyl group, A denotes a nitrogen atom or a methine group, and n stands for an integer of 1-5, which comprises reducing an azolylmethyloxabicyclohexane derivative represented by the general formula (VI) ##STR2## wherein R 1 , R 2 , R, A and n have the same meanings as defined above. A fungicidal composition comprising the azolylmethyloxabicyclohexane derivative represented by the above-mentioned general formula (VI) is also desclosed.

This application is a division of application Ser. No. 07/798,716, filedNov. 29, 1991 now U.S. Pat. No. 5,225,430, issued Jul. 6, 1993.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for - selectively preparingracemic or optically active cis-azole derivatives which are activeingredients of agricultural and horticultural compositions, and tointermediates for preparing the azole derivatives, a process forpreparation thereof, and fungicidal compositions.

2. Description of the Related Art

Azole derivatives represented by the following general formula (I) haveheretofore been known to have excellent agricultural and horticulturalfungicidal effects and plant growth controlling effects, and a processfor preparation thereof has been known too. ##STR3## wherein R¹ and R²mean a hydrogen atom or an alkyl group, independently, R denotes ahalogen atom, a nitro group, independently, R denotes a halogen atom, anitro group, a cyano group, an alkyl group, a haloalkyl group or aphenyl group, A denotes a nitrogen atom or a methine group, and n standsfor 0 or an integer of 1-5.

Namely, EP-A-329397 discloses a process for preparation of a racemicmixture of cis-azole derivatives and trans-azole derivatives representedby the above general formula (I), and EP-A-267778 discloses a processfor preparation of cis- or trans-azole derivatives represented by thegeneral formula (I') ##STR4## wherein R^(1') and R^(2') denote each a C₁-C₅ alkyl group or a hydrogen atom, but R^(1') and R^(2') are nothydrogen atom at the same time, X' denotes a halogen atom, a C₁ -C₅alkyl group or a phenyl group, n' stands for 0 or an integer of 1 or 2,and A' denotes a nitrogen atom or a methine group, which comprises usingcis- or trans-oxaspiroheptane derivatives represented by the generalformula (II') ##STR5## wherein R^(1') and R^(2'), X' and n have the samemeanings as defined above.

It has been known that the azole derivatives represented by the generalformula (I) has a higher activity in the cis form than in the transform.

It is therefore desired to provide a process by which cis-form azolederivatives represented by the general formula (I) having a higherfungicidal activity are selectively prepared. In the process describedin EP-A-329397, however, since a mixture of cis form and tans form isprepared, the yield of the cis form is reduced under the influence ofthe by-produced trans form and it is necessary to separate the cis-azolederivatives from the mixture of the cis form and trans form. Further, inthe process described in Japanese Patent Application Laid-Open No.93574/1989, a process for separating the cis form is required in a stageof preparing oxaspiroheptane derivatives represented by the generalformula (II') in order to obtain the cis azole derivatives.

As be described above, the prior processes require a separation step forobtaining purified cis form. In the separation step, large amounts ofcolumn packings or solvents are used and a loss is caused whenseparation is carried out. Accordingly, it is not advantageous tocombine the separation step in the industrial process for preparation ofthe cis form.

The present invention has been achieved in the light of the abovedescribed circumstances in the prior arts.

SUMMARY OF THE INVENTION

An object of the present invention is therefore to provide a process forselectively preparing cis-azole derivatives represented by the generalformula (I) which show reliable effects in a smaller amount because ofhaving a high fungicidal activity, by which the amount existent in theenvironment becomes small.

Another object of the present invention is to provide intermediatesuseful for producing the cis-azole derivatives

A further object of the present invention is to provide prosesses forpreparation of the intermediates.

A still further object of the present invention is to provide afungicidal composition.

The present inventors have noticed the fact that the cis-azolederivatives represented by the general formula (I) has a highereffectiveness as compared with trans-azole derivatives which aregeometrical isomers. As a result of earnest studies concerning theprocess for selective preparation in order to solve the above mentionedproblems, it has found a process by which only cis form can be prepared,leading to completion of this invention.

With respect to configuration of the azole derivatives represented bythe general formula (I) in the present specification, cis form meansthose wherein a substituted or non-substituted phenylmethyl group isbonded to the cis position of the hydroxyl group attached on thecyclopentane ring, and trans form means those wherein said group isbonded to the trans position of the hydroxyl group attached on thecyclopentane ring.

The characteristic of the present invention is as follows.

In one aspect of this invention, there is thus provided a process forpreparing a cis-azole derivatives represented by the general formula (I)##STR6## wherein R¹ and R² denote each a hydrogen atom or an alkylgroup, R denotes a halogen atom, a nitro group, a cyano group, an alkylgroup, a haloalkyl group or a phenyl group, A denotes a nitrogen atom ora methine group, and n stands for 0 or an integer of 1-5, whichcomprises subjecting an oxaspiroheptane derivative represented by thegeneral formula (II) to a rearrangement reaction ##STR7## wherein R¹,R², R, and n have the same meanings as defined above, epoxidating theresultant cyclopentenemethanol derivative represented by the generalformula (III) ##STR8## wherein R¹, R², R, and n have the same meaningsas defined above, conducting sulfonic esterification of the resultantoxabicyclohexanemetanol derivative represented by the general formula(IV) ##STR9## wherein R¹, R², R, and n have the same meanings as definedabove, sujecting to a substitution reaction the resultantoxabicyclohexanemethanol sulfonic acid ester derivative represented bythe general formula (V) with a 1,2,4-triazole or imidazole ##STR10##wherein R¹, R², R, and n have the same meanings as defined above, and Ydenotes an alkyl group or a nonsubstituted or substituted phenyl group,and reducing the resultant azolylmethyloxabicyclohexane derivativerepresented by the general formula (VI) ##STR11## wherein R¹, R², R, Aand n have the same meanings as defined above.

In another aspect of this invention, there is also provided a processfor preparing a cis-azole derivatives represented by the above-mentionedgeneral formula (I) which comprises reducing anazolylmethyloxabicyclohexane derivative represented by the generalformula (VI) ##STR12## wherein R¹, R², R, A and n have the same meaningsas defined above.

In a further aspect of this invention, there is also provided anazolylmethyloxabicyclohexane derivative represented by the generalformula (VI) ##STR13## wherein R¹, R², R, A and n have the see meaningsas defined above.

In a further aspect of this invention, there is also provided a processfor preparing an azolylmethyloxabicyclohexane derivative represented bythe above described general formula (VI) which comprises subjecting to asubstitution reaction an oxabicyclohexanemethanol sulfonic acid esterderivative represented by the general formula (V) with a 1,2,4-triazoleor an imidazole. ##STR14## wherein R¹, R², R, and n have the samemeanings as defined above, and Y denotes an alkyl group or anonsubstituted or substituted phenyl group.

In a further aspect of this invention, there is also provided anoxabicyclohexanemetanol sulfonic acid ester derivative represented bythe general formula (V) ##STR15## wherein R¹, R², R, n and Y have thesame meanings as defined above.

In a further aspect of this invention, there is also provided a processfor preparing an oxabicyclohexanemetanol sulfonic acid ester derivativesrepresented by the above described formula (V) which comprisesconducting sulfonic esterification of an oxabicyclohexanemethanolderivative represented by the general formula (IV) ##STR16## wherein R¹,R², R, and n have the same meanings as defined above.

In a further aspect of this invention, there is also provided anoptically active oxabicyclohexanemethanol derivative represented by thegeneral formula (IV) ##STR17## wherein R¹, R², R, and n have the samemeanings as defined above.

In a further aspect of this invention, there is also provided a processfor preparing an oxabicyclohexanemethanol derivative represented by theabove described general formula (IV) which comprises epoxidating acyclopentenemethanol derivative represented by the general formula (III)##STR18## wherein R¹, R², R, and n have the same meanings as definedabove.

In a further aspect of this invention, there is also provided acyclopentenemethanol derivative represented by the general formula (III)##STR19## wherein R¹, R², R, and n have the same meanings as definedabove.

In a further aspect of this invention, there is also provided a processfor preparing a cyclopentenemethanol derivative represented by the abovedescribed general formula (III) which comprises subjecting anoxaspiroheptane derivative represented by the general formula (II) to arearrangement reaction ##STR20## wherein R¹, R², R, and n have the samemeanings as defined above.

In a still further aspect of this invention, there is also provided afungicidal composition comprising as an effective ingredient anazolylmethyloxabicyclo-hexane derivative represented by the followingformula (VI) together with an inert carrier or adjuvants; ##STR21##wherein R¹, R², R, A and n have the same meanings as defined above.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The process for preparing the cis-azole derivative represented by theabove described general formula (I) is shown as the following reactionformulas. ##STR22##

In the following, the present invention will be illustrated in greaterdetail.

The cis-azole derivative represented by the general formula (I) andintermediates thereof of the present invention will be first explained.In the azole derivatives represented by the above-mentioned generalformula (I), R¹ and R² mean a hydrogen atom or an alkyl group andpreferably a hydrogen atom or an C₁ -C₃ alkyl group. R means a halogenatom, a nitro group, a cyano group, an alkyl group, a haloalkyl group ora phenyl group, and preferably a chlorine atom bonded to the 4-position.

n is 0 or an integer or from 1 to 5 and preferably 0-1. A means anitrogen atom or a methine group.

In the intermediates represented by the above-mentioned general formulas(II), (III), (IV), (V) and (VI), the substituents R¹, R² and R, n and Ahave the same meanings as those in the azole derivative represented bythe general formula (I), and preferred embodiments are also the same. Inthe oxabicyclohexanemethanol sulfonic acid ester derivative representedby the general formula. (V) , Y means an alkyl group or a nonsubstitutedor substituted phenyl group, and preferably a C₁ -C₄ alkyl group, aphenyl group or a p-methylphenyl group. The process of the presentinvention will be explained in the following in accordance with theabove-mentioned reaction formulas.

Rearrangement Reaction

The oxaspiroheptane derivative represented by the general formula (II)can be changed into the cyclopentene methanol derivatives represented bythe general formula (III) by a rearrangement reaction in a presence ofan acid catalyst in an organic solvent at a reaction temperature in arange of from 0° C. to 40° C. for a reaction time in a range of from 1hour to 5 hours. As the organic solvent, ethers can be used.Particularly preferred examples include dioxane, tetrahydrofuran (THF)and diethyl ether. As the acid catalyst, it is possible to use, forexample, sulfuric acid, hydrochloric acid, AlCl₃, BF₃ and the like.

Epoxidation Reaction

The oxabicyclohexanemethanol derivative represented by the generalformula (IV) is obtained by epoxidation of the cyclopentenemethanolderivative represented by the general formula (III) using an inorganicor organic peroxide in an organic solvent at a reaction temperature in arange of from -78° C. to 25° C. for a reaction time in a range of from 1hour to 5 hours.

Examples of the organic solvents include alkyl halides such asdichloromethane or dichloroethane etc., aromatic hydrocarbons such astoluene etc., aliphatic hydrocarbons such as hexane, heptane orisooctane etc. As the peroxide, it is possible to usemetachloroperbenzoic acid, cumene hydroperoxide and tertiary butylhydroperoxide and the like.

Furthermore, when the epoxidation is carried out using an asymmetricreagent, it is possible to obtain an optically activeoxabicyclohexanemethanol derivative represented by the general formula(IV). For example, an optically active (+)-oxabicyclohexanemethanolderivative represented by the general formula (IV) can be obtained bycarrying out the epoxidation reaction using as an asymmetric reagent acombination of (2R,3R)-(+)-diethyl tartarate and titaniumtetraisopropoxide. Likewise, an optically active(-)-oxabicyclohexanemethanol derivative represented by the generalformula (IV) can be obtained by carrying out the epoxidation reactionusing as an asymmetric reagent a combination of (2S,3S)-(-)-diethyltartarate and titanium tetraisopropoxide.

In such cases, the above-mentioned combination of the reagents can beused together with Molecular seives.

Using the thus resulted optically active oxabicyclohexanemethanolderivative represented by the general formula (IV), the optically activecis-azole derivative represented by the general formula (I) can beprepared by the sulfonic esterification, the azolation reaction and thereduction reaction in accordance with the above-mentioned chemicalformulas as follows.

Sulfonic esterification reaction

The oxabicyclohexanemethanol sulfonic acid ester derivatives can beobtained by subjecting the oxabicyclohexanemethanol derivativerepresented by the general formula (V) to sulfonic esterification in anorganic solvent using benzenesulfonyl chloride, substitutedbenzenesulfonyl chloride or alkanesulfonyl chloride and a hydrochloricacid binding agent at a reaction temperature in a range of from 0° C. to40° C. for a reaction time in a range of from 0.5 hours to 5 hours.

A preferred example of the substituted benzenesulfonyl chloride isp-methylbenzenesulfonyl chloride, and a preferred example of thealkanesulfonyl chloride is methanesulfonyl chloride.

Examples of the hydrochloric acid binding agent include trimethylamine,triethylamine, N,N-dimethylaniline and N,N-diethylaniline, etc., but thepresent invention is not limited to using them.

Examples of the organic solvent include aromatic hydrocarbons such asbenzene, toluene and xylene, etc., aliphatic hydrocarbons such ashexane, heptane and isooctane etc., alkyl halides such asdichlorometane, chloroform, carbon tetrachloride and dichloroethane,etc., and ethers such as dioxane, THF and diethyl ether etc.

Azolation Reaction

The azolylmethyloxabicyclohexane derivative represented by the generalformula (VI) can be obtained by reacting the oxabicyclohexanemethanolsulfonic acid ester represented by the general formula (V) with a1,2,4-triazole or an imidazole, and a base compound in an organicsolvent at a reaction temperature in a range of from 0° C. to 100° C.for a reaction period in a range of from 1 hour to 5 hours to substitutea YSO₂ O group with an azole ring.

As the base compound, sodium hydride may be preferably used.

Preferred example of the organic solvent used in this reaction stepinclude aromatic hydrocarbons such as benzene, toluene and xylene etc.,aliphatic hydrocarbons such as hexane, heptane and isooctane, etc.,alkyl halides such as dichloromethane, chloroform, carbon tetrachlorideand dichloroethane etc., ethers such as dioxane, THF and diethyl ether,etc., alcohols such as methyl alcohol, ethyl alcohol, etc., and polaraprotic solvents such as acetonitrile, acetone, DMF, DMSO andN-methylpyrrolidone etc.

Reduction Reaction

The cis-azole derivative represented by the general formula (I) can beobtained by reducing the azolylmethyloxabicyclohexane derivatives in anether using a metal hydride or a combination of metal hydride and Lewisacid at a reaction temperature in a range of from 0° to 100° C. for areaction period in a range of from 0.5 hours to 5 hours.

Examples of the ethers used in this reaction step include diethyl ether,THF and diglym. As the metal hydride, lithium aluminium hydride may bepreferably used. An example of the Lewis acid used together with themetal hydride is AlCl₃.

According to the process of the present invention, cis-azole derivativesrepresented by the above mentioned general formula (I) which showreliable effects in a smaller amount because of having a higheractivity, by which the amount existent in the environment becomes small,can be selectively prepared.

As a result of studies by the present inventors about the use, it hasbeen found that the above-mentioned azolylmethyloxabicyclohexanerepresented by the general formula (VI) can be used as fungicides inaddition to as the intermediate.

In the following, use of the azolylmethyloxabicyclohexane derivativerepresented by the formula (VI) as a fungicide ##STR23## wherein R¹, R²,R, A and n have the same meanings as defined above.

When the azolylmethyloxabicyclohexane derivative represented by theformula (VI) (referred to as "compound of this invention", hereinafter)is used as a fungicidal composition, it is generally used in the form ofdust, wettable powder, granules, emulsion and the like together withcarriers or other adjuvants. In such a case, the preparations areprepared so as to contain one or more of the compound of this inventionin an amount of 0.1%-95% by weight , preferably, 0.5%-90% by weight, andmore preferably 2%-70% by weight.

Examples of carriers, diluents and surfactants used as the adjuvants forpreparations include the following.

Examples of solid carriers include talc, kaolin, bentonite, diatomaceousearth, white carbon and clay, etc.

Examples of liquid carriers (diluents) include water, xylene, toluene,chlorobenzene, cyclohexane, cyclohexanone, dimethylsulfoxide,dimethylformamide and alcohol, etc.

Examples of the surfactants include polyoxyethylene alkylaryl ether andpolyoxyethylene sorbitan monolaurylate etc., as emulsifiers; ligninsulfonates, dibutylnaphthalenesulfonates, etc., as dispersing agents;and alkylsulfonates and alkylphenylsulfonates, etc., as wetting agents.

The above preparations are classified into those which can be useddirectly, and those which are used after diluting so as to have asuitable concentration with a diluent such as water, etc.

The concentration of the present compounds in case of using afterdiluting is preferred to be in a range of 0.001%-1.0%.

Further, the application dosage of the compound of this invention is ina range of 20 g-5000 g and preferably 50 g-1000 g per 1 ha ofagricultural and horticultural land such as farm, paddy field, fruitgarden, hothouse, etc.

It is of course possible to increase and decrease the concentration andthe application dosage beyond the above-mentioned ranges, because theydepend upon the form of preparations, method of application, place to beused, target crops, etc.

Furthermore, the compound of this invention can be used in combinationwith other effective ingredients, such as other fungicides,insecticides, miticides, herbicides, etc.

EXAMPLES

Preparation examples, formulation examples and test examples aredescribed in the following, by which the present invention isillustrated in detail.

Preparation examples 6 and 10 and Preparation examples 14, 15, 16, 17and 18 in the examples relates to preparation of optically activeepoxyalcohol derivatives.

Preparation examples 14-18 disclose the process in which a reagent forasymmetric epoxidation is used together with Molecular Sieves.

Further, the following abbreviations and chemical formulas are used inPreparation examples 6, 10, 14, 15, 16, 17 and 18.

    ______________________________________                                        (2R,3R)-(+)-diethyl tartarate                                                                        (+)-DET                                                (2S,3S)-(-)-diethyl tartarate                                                                        (-)-DET                                                Titanium tetraisopropoxide                                                                           Ti(O i-Pr).sub.4                                       tert-Butylhydroperoxide                                                                              TBHP                                                   ______________________________________                                    

Enantiomer excess ratio (% ee) described in Preparation examples 6, 9,10, 13, 14, 15, 16, 17 and 18 was determined by high performance liquidchromatography equipped with an optically active column (CHIRALCEL OK,produced by Daicel Co.).

Preparation Example 1

Cyclopentene methanol derivative [Formula (III): R¹ =R² =CH₃, (R)_(n)=4-Cl]

Preparation of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol:

To 20 g (0.08 mol) of7-[(4-chlorophenyl)methyl]-4,4-dimethyl-1-oxaspiro[2.4]heptane[Formula(II): R¹ =R² =CH₃, (R)_(n) =4-Cl ] was added 150 ml of dioxane,and 5 ml of 10% sulfuric acid was added thereto with stirring under roomtemperature. The mixture was then stirred at room temperature for 2hours.

The reaction solution was poured into a saturated aqueous solution ofsodium hydrogen carbonate, followed by extracting with ethyl acetate.The resultant organic layer was washed with saturated aqueous salinesolution.

After dried with anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure to yield 17.22 g of a yellowish oilyproduct.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 13.16 g (0.052 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] as a colorless transparentoily product.

Yield: 65.8%.

Colorless transparent oil.

¹ H NMR(CDCl₃); δ 1.10 (s,6H), 1.40-1.83 (m,2H), 1.97-2.33 (m,2H), 3.43(s,2H), 4.22 (s,2H), 7.03 (d,2H, J=8 Hz), 7.23 (d,2H, J=8 Hz).

IR(neat, νmax); 3350, 2950, 2850, 1490, 1408, 1360, 1090, 1012, 990, 840cm⁻¹.

Preparation Example 2

Oxabicyclohexanemethanol derivative [Formula (IV): R¹ =R² =CH₃ , (R)_(n)=4-Cl]

Preparation of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

10.06 g (0.04 mol) of2-[(4-chlorophenyl)methyl]5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] were dissolved in 100 ml ofchloroform, followed by adding 8.08 g (0.048 mol) ofmetachloroperbenzoic acid with stirring under cooling with ice.

The mixture was then stirred at room temperature for 1 hour. To thereaction solution was added 7.4 g (0.1 mol) of calcium hydroxide, andthe formed precipitate was removed by filtration. The chloroform layerwas washed with a saturated aqueous saline solution.

After the chloroform layer was dried with anhydrous sodium sulfate, itwas concentrated under reduced pressure to yield 11.86 g oflight-yellowish oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 10.21 g (0.038 mmol) of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 95%.

White crystal, m.p.: 37-39° C.

¹ H NMR(CDCl₃); δ 0.9 (s, 3H), 1.10 (s, 3H), 1.0-1.83 (m, 4H), 2.43(brs, 1H, OH), 3.0 (s,2H), 3.8 (d, 1H, J=12 Hz),4.1 (d, 1H, J=12 Hz),7.13 (m,4H)

IR(KBr, νmax); 3400, 2950, 2850, 1482, 1360, 1082, 1010, 836, 780cm⁻¹.

Preparation Example 3

Oxabicyclohexanemethanol sulfonic acid ester derivative [Formula (V): R¹=R² =CH₃, (R)_(n) =4-Cl, Y=CH₃ ]

Preparation of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester:

1.33 g (5 mmol) of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolwere dissolved in 10 ml of dichloromethane, followed by adding thereto0.63 g (5.5 mmol) of methanesulfonyl chloride and 0.55 g (5.65 mmol) oftriethylamine with stirring under cooling with ice.

The mixture was then stirred under cooling with ice for 1 hour. Afterconclusion of the reaction was confirmed by TLC, the reaction solutionwas poured into water and extracted with dichlorometane. The resultantorganic layer was washed with aqueous solution of saturated sodiumhydrogen carbonate and aqueous saline solution.

After dried with anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure to yield 1.86 g of a light-yellowishoily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 1.57 g (4.55 mmol) of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4-Cl,Y=CH₃ ].

Yield: 91%.

White crystal, m.p. 78.5-79.0° C.

¹ H NMR(CDCl₃); δ0.98 (s,3H), 1.10 (s,3H), 0.83-2.0 (m,4H), 2.93 (s,2H),3.07 (s, 3H), 4.37 (d, 1H, J=12 Hz), 4.70 (d, 1H, J=12 Hz), 7.07 (d, 2H,J=8 Hz), 7.25 (d, 2H, J=8 Hz).

IR(KBr, νmax); 3000, 2940, 2850, 1480, 1350, 1162, 1080, 944, 810 cm⁻¹.

Preparation Example 4

Azolylmethyloxabicyclohexane derivative [Formula(VI): R¹ =R² =CH₃,(R)_(n) =4-Cl, A=N].

Preparation of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane(Compound No. VI-1):

To 0.42 g (10.5 mmol) of oily 60% sodium hydride washed with hexane wasadded 15 ml of dimethylformamide (DMF) and stirred at room temperature.0.73 g (10.56 mmol) of 1,2,4-triazole were then added thereto. After themixture was stirred for 30 minutes, 5 ml of a DMF solution containing3.05 g (8.8 mmol) of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4-Cl,Y-CH₃ ] was added dropwise thereto.

Thereafter, the mixture was stirred at room temperature for 4 hours andat 40° C. for 4 hours, and the reaction solution was poured into icewater, followed by extracting with ethyl acetate. The resultant organiclayer was washed with 1N-hydrochloric acid, saturated aqueous solutionof sodium hydrogen carbonate and saturated aqueous saline solution.After dried with anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure to yield 2.88 g of a light-yellowishoily product.

The resultant oily product was purified by chromatography on a column ofsilica gel, followed by crystallizing with hexane to obtain 2.71 g (8.5mmol) of 5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo [3.1.0]hexane as white crystal[Formula (VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N].

Yield: 96.6%.

White crystal, m.p. 101.5-102.5° C.

¹ H NMR (CDCl₃); δ 0.73 (s,3H), 1.0 (s,3H), 0.83-2.17 (m,4H), 2.93(s,2H), 3.07 (s, 3H), 4.33 (d, 1H, J=16 Hz), 4.87 (d, 1H, J=16 Hz), 7.17(d,2H, J=8 Hz), 7.33 (d,2H, J=8 Hz), 7.93 (s, 1H), 8.33 (s, 1H).

IR(KBr, νmax); 3100, 2940, 2850, 1480, 1420, 1260, 1200, 1130, 1084,1020, 950, 840, 720, 660cm⁻¹.

With the same procedure as preparation example 4, except using animidazole in stead of a 1,2,4-triazole,5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane(Compound No. VI-2) can be prepared.

Preparation Example 5

Cis-azole derivative [Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N]

Preparation ofcis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol:

To 210 mg (1.57 mmol) of aluminium chloride was added 5 ml ofdimethoxyethane (DME) and stirred at room temperature. To the mixturewas added 178.7 mg (4.71 mmol) of lithium aluminium hydride and stirredfor 30 minutes with elevating the temperature to 50° C. 500 mg (1.57mmol) of5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane[Formula (VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N] was added to the mixtureand stirred at 50° C. for 1 hour.

The reaction solution was poured into 50 ml of ice water and extractedwith ethyl acetate. The separated organic layer was washed withsaturated aqueous saline solution. After dried with anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure toyield 580 mg of a yellowish oily product.

The resultant oily product was isolated and purified by chromatographyon a column of silica gel to obtain 280.3 mg (0.88 mmol) ofcis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol[Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N].

Yield: 55.4%.

White crystal, m.p. 113-114° C.

¹ H NMR (CDCl₃); δ 0.60 (s,3H), 1.00 (s,3H), 1.07-1.90 (m,5H), 2.33(bs,2H), 3.53 (s,1H), 4.13 (s,2H), 7.06 (d,2H, J=8 Hz), 7.25 (d,2H, J=8Hz) , 8.02 (s, 1H) , 8.25 (s, 1H).

IR(KBr, νmax); 3250, 2940, 2850, 1480, 1380, 1262, 1200, 1124, 1080,1002, 840, 800, 720, 670 cm⁻¹.

With the same procedure as preparation example 5, except using thecompound (VI-2) instead of the compound (VI-1),cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)cyclopentanolcan be prepared.

Preparation Example 6

Optically active (+)-oxabicyclohexamethanol derivative [Formula (IV): R¹=R² =CH₃, (R)_(n) =4-Cl, ]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

1.42 g (5 mmol) of Ti(O i-Pr) were dissolved in 15 ml of dichloromethaneand stirred at -20° C. (dry ice/carbon tetrachloride) under a nitrogenstream. To the mixture was added 1.03 g (5 mmol) of (+)-DET and 1.25 g(5 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl]. After stirred at -20° C.for 5 minutes, 6 ml (10 mmol) of a toluene solution of anhydrous TBHP(1.67 mol/l) was added dropwise thereto. The reaction concluded at -20°C. for 1 hour. After stirred at room temperature for 60 minutes, 6 ml of30% sodium hydroxide-saturated aqueous solution of sodium chloride wereadded to the resulted mixture and stirred for further 30 minutes. Afterallowed to stand for a while by adding 1 ml of methanol, the formedorganic layer was separated. The aqueous layer was extracted withdichloromethane. The separated organic layers were combined, dried withanhydrous sodium sulfate, and concentrated under reduced pressure toyield 1.35 g of a light-yellowish oily product.

The resultant oily product was purified by chromatography on a column ofsilica gel to obtain 1.16 g (4.35 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 87%.

Colorless transparent oil.

[α]_(D) ²⁰ +25.4° (c=1.26, EtOH): 91% ee (by HPLC).

¹ H NMR(CDCl₃); δ 0.9 (s,3H), 1.10 (s,3H), 1.0-1.83 (m,4H), 2.43 (s,1H),3.0 (s,2H), 3.8 (d, 1H, J=12 Hz), 4.1 (d, 1H, J=12 Hz), 7.13 (m,4H)

IR (neat, νmax); 3400, 2950, 2850, 1482, 1360, 1082, 1010, 836, 780cm⁻¹.

Preparation Example 7

Optically active (+)-oxabicyclohexanemethanol sulfonic acid ester[Formula(V): R¹ =R² =CH₃, (R)_(n) =4-Cl, Y=CH₃ ]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester:

0.84 g (3.15 mmol) of (+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo [3.1.0]hexane-1-methanol [Formula(IV): R¹ =R² =CH₃, (R)_(n) =4-Cl] were dissolved in 10 ml ofdichloromethane, followed by adding 0.41 g (3.5 mmol) of methanesulfonylchloride and 0.3 g (3.5 mmol) of triethylamine were added thereto withstirring under cooling with ice.

The mixture was then stirred under cooling with ice for 1 hour. Afterconclusion of the reaction was confirmed by TLC, the reaction solutionwas poured into water and extracted with dichlorometane. The resultantorganic layer was washed with aqueous solution of saturated sodiumhydrogen carbonate and aqueous common salt liquor. After dried withanhydrous sodium sulfate, the organic layer was concentrated underreduced pressure to yield 1.22 g of a light-yellowish oily product.

The resultant oily product was purified by chromatography on a column ofsilica gel to obtain 1.02 g (2.96 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4-Cl,Y=CH₃ ].

Yield: 94%.

Colorless transparent oil.

[α]_(D) ²⁰ +24° (c=1.08, EtOH).

¹ H NMR (CDCl₃); δ 0.98 (s, 3H), 1.10 (s, 3H), 0.83-2.0 (m, 4H), 2.93(s, 2H), 3.07 (s, 3H) , 4.37 (d, 1H, J=12 Hz ), 4.70 (d,1H, J=12 Hz),7.07 (d,2H, J=8 Hz), 7.25 (d,2H, J=8 Hz).

IR(neat, νmax); 3000, 2940, 2850, 1480, 1350, 1162, 1080, 944, 810cm⁻¹.

Preparation Example 8

Optically active (-)-azolylmethyloxabicyclohexane derivative [Formula(VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N]

Preparation of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane(Compound No. VI-3):

To 0.12 g (3.0 mmol) of oily 60% sodium hydride

washed with hexane was added 5 ml of DMF and stirred at roomtemperature. 0.21 g (3.0 mmol) of 1,2,4-triazole were then addedthereto. After the mixture was stirred for 10 minutes, 2 ml of a DMFsolution containing 0.86 g (2.5 mmol) of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4-Cl,Y=CH₃ ] was added dropwise thereto.

Thereafter, the mixture was stirred at room temperature for 1 hour andat 40° C. for 4 hours, and the reaction solution was poured into icewater, followed by extracting with ethyl acetate. The resultant organiclayer was washed with 1N-hydrochloric acid, saturated aqueous solutionof sodium hydrogen carbonate and saturated aqueous salinel solution.After dried with anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure to yield 0.82 g of a light-yellowishoily product.

The resultant oily product was purified by chromatography on a column ofsilica gel, followed by crystallizing with hexane to obtain 0.77 g (2.42mmol) of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo [3.1.0]hexane as white crystal [Formula (VI): R¹ =R²=CH₃, (R)_(n) =4-Cl, A=N ].

Yield: 96.8%.

[α]_(D) ²⁰ -11° (c=1.0, EtOH).

White crystal, m.p. 97-99° C.

¹ H NMR(CDCl₃); δ 0.73 (s,3H) 1.0 (s,3H), 0.83-2.17 (m, 4H), 2.93 (s,2H), 3.07 (s, 3H), 4.33 (d, 1H, J=16 Hz), 4.87 (d, 1H, J=16 Hz), 7.17(d,2H, J=8 Hz), 7.33 (d,2H, J=8 Hz), 7.93 (s,1H), 8.33 (s, 1H).

IR(KBr, νmax); 3100, 2940, 2850, 1480, 1420, 1260, 1200, 1130, 1084,1020, 950, 840, 720, 660 cm⁻¹.

With the same procedure as preparation example 8, except using animidazole in stead of a 1,2,4-triazole,(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane(Compound No. VI-4) can be prepared.

Preparation Example 9

Optically active cis-azole derivative [Formula (I): R¹ =R² =CH₃, (R)_(n)=4-Cl, A=N]

Preparation of(-)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-cyclopentanol:

To 212.4 mg (1.59 mmol) of aluminium chloride was added 5 ml ofdimethoxyethane (DME) and stirred at room temperature. To the mixturewas added 181.6 mg (4.78 mmol) of lithium aluminium hydride and stirredfor 30 minutes with elevating the temperature to 50° C. 503.7 mg (1.58mmol) of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane [Formula (VI): R¹ =R² =CH₃, (R)_(n) =4-Cl,A=N] were added to the mixture and stirred at 50° C. for 1 hour.

The reaction solution was poured into 50 ml of ice water and extractedwith ethyl acetate. The separated organic layer was washed withsaturated aqueous saline solution. After dried with anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure toyield 550 mg of a yellowish oily product.

The resultant oily product was isolated and purified by chromatographyon a column of silica gel to obtain 267.4 mg (0.836 mmol) of(-)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol[Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N ].

Yield: 52.9%.

White crystal, m.p. 137-138° C. (recrystallization from n-hexane/ethylacetate-10/1).

[α]_(D) ²⁰ -23.7° (c=10.0, EtOH): 99% ee (by HPLC).

¹ H NMR(CDCl₃); δ 0.60 (s, 3H), 1.00 (s, 3H), 1.07-1.90 (m, 5H), 2.33(bs, 2H), 3.53 (s,1H), 4.13 (s,2H), 7.06 (d,2H, J=8 Hz), 7.25 (d,2H, J=8Hz), 8.02 (s,1H), 8.25 (s,1H).

IR(KBr, νmax); 3250, 2940, 2850, 1480, 1380, 1262, 1200, 1124, 1080,1002, 840, 800, 720, 670 cm⁻¹.

With the same procedure as preparation example 9, except using thecompound (VI-4) instead of the compound (VI-3),(-)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)cyclopentanolcan be prepared.

Preparation Example 10

Optically active (-)-oxabicyclohexamethanol derivative [Formula (IV): R¹=R² =CH₃, (R)_(n) =4-Cl]

Preparation of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

1.42 g (5 mmol) of Ti(O i-Pr) were dissolved in 15 ml of dichloromethaneand stirred at -20° C. (dry ice/carbon tetrachloride) under a nitrogenstream. To the mixture was added 1.03 g (5 mmol) of (-)-DET and 1.25 g(5 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl]. After stirred at -20° for 5minutes, 6 ml (10 mmol) of a toluene solution of anhydrous TBHP (1.67mol/l) was added dropwise thereto. The reaction concluded at -20° for 1hour. After stirred at room temperature for 60 minutes, 6 ml of 30%sodium hydroxide-saturated aqueous solution of common salt were added tothe resulted mixture and stirred for further 30 minutes. After allowedto stand for a while by adding 1 ml of methanol, the formed organiclayer was separated. The aqueous layer was extracted withdichloromethane. The separated organic layers were combined, dried withanhydrous sodium sulfate, and concentrated under reduced pressure toyield 1.40 g of a light-yellowish oily product.

The resultant oily product was purified by chromatography on a column ofsilica gel to obtain 1.16 g (4.35 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 81%.

Colorless transparent oil.

[α]_(D) ²⁰ -25.0° (c=1.64 EtOH): 98.8% ee (by HPLC).

¹ H NMR (CDCl₃); δ 0.9 (s,3H), 1.10 (s,3H) 1.0-1.83 (m,4H), 2.43 (s,1H),3.0 (s,2H), 3.8 (d, 1H, J=12 Hz), 4.1 (d, 1H, J=12 Hz), 7.13 (m, 4H).

IR(neat, νmax); 3400, 2950, 2850, 1482, 1360, 1082, 1010, 836, 780 cm⁻¹.

Preparation Example 11

Optically active (-) -oxabicyclohexanemethanol sulfonic acid ester[Formula(V): R¹ =R² =CH₃, (R)_(n) =4-Cl, Y=CH₃ ]

Preparation of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester:

0.93 g (3.48 mmol) of(-)-5-[(4-chlorophenyl)-methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl] were dissolved in 10 ml ofdichloromethane, followed by adding 0.44 g (3.8 mmol) of methanesulfonylchloride and 0.38 g (3.8 mmol) of triethylamine were added thereto withstirring under cooling with ice.

The mixture was then stirred under cooling with ice for 1 hour. Afterconclusion of the reaction was confirmed by TLC, the reaction solutionwas poured into water and extracted with dichlorometane. The resultantorganic layer was washed with aqueous solution of saturated sodiumhydrogen carbonate and aqueous common salt liquor. After dried withanhydrous sodium sulfate, the organic layer was concentrated underreduced pressure to yield 1.27 g of a light-yellowish oily product.

The resultant oily product was purified by chromatography on a column ofsilica gel to obtain 1.14 g (3.3 mmol) of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4

Y=CH₃ ].

Yield: 95%.

Colorless transparent oil.

[α]_(D) ²⁰ -24.50° (c=1.2, EtOH).

¹ H NMR(CDCl₃); δ 0.98 (s,3H), 1.10 (s,3H), 0.83-2.0 (m,4H), 2.93(s,2H), 3.07 (s,3H), 4.37 (d, 1H, J=12 Hz), 4.70 (d, 1H, J=12 Hz), 7.07(d,2H, J=8 Hz), 7.25 (d,2H, J=8 Hz).

IR(neat, νmax); 3000, 2940, 2850, 1480, 1350, 1162, 1080, 944, 810 cm⁻¹.

Preparation Example 12

Optically active (+)-azolylmethyloxabicyclohexane derivative [Formula(VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N]

Preparation of (+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane (Compound No.VI-5):

To 0.14 g (3.5 mmol) of oily 60% sodium hydride washed with hexane wasadded 5 ml of dimethylformamide (DMF) and stirred at room temperature.0.25 g (3.6 mmol) of 1,2,4-triazole were then added thereto. After themixture was stirred for 10 minutes, 2 ml of a DMF solution containing1.03 g (3.0 mmol) of(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]-hexane-1-methanolmethanesulfonic acid ester [Formula (V): R¹ =R² =CH₃, (R)_(n) =4-Cl,Y=CH₃ ] was added dropwise thereto.

Thereafter, the mixture was stirred at room temperature for 1 hour andat 40° C. for 4 hours, and the reaction solution was poured into icewater, followed by extracting with ethyl acetate. The resultant organiclayer was washed with 1N-hydrochloric acid, saturated aqueous solutionof sodium hydrogen carbonate and saturated aqueous saline solution.After dried with anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure to yield 1.05 g of a light-yellowishoily product.

The resultant oily product was purified by chromatography on a column ofsilica gel, followed by crystallizing with hexane to obtain 0.89 g (2.8mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexaneas white crystal [Formula (VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N].

Yield: 93.3%.

[α]_(D) ²⁰ +12° (c=1.0, EtOH).

White crystal, m.p. 97-99° C.

¹ H NMR(CDCl₃); δ 0.73 (s,3H), 1.0 (s,3H), 0.83-2.17 (m,4H), 2.93(s,2H), 3.07 (s,3H), 4.33 (d, 1H, J=16 Hz), 4.87 (d, 1H, J=16 Hz), 7.17(d,2H, J=8 Hz), 7.33 (d,2H, J=8 Hz), 7.93 (s,1H), 8.33 (s,1H) IR(KBr,νmax); 3100, 2940, 2850, 1480, 1420, 1260, 1200, 1130, 1084, 1020, 950,840, 720, 660 cm⁻¹.

With the same procedure as preparation example 12, except using animidazole in stead of a 1,2,4-triazole,(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane(Compound No. VI-6) can be prepared.

Preparation Example 13

Optically active cis-azole derivative [Formula (I): R¹ =R² =CH₃, (R)_(n)32 4-Cl, A=N]

Preparation of(+)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-cyclopentanol

To 0.27 g (2.0 mmol) of aluminium chloride was added 5 ml ofdimethoxyethane (DME) and stirred at room temperature. To the mixturewas added 0.23 g (6.1 mmol) of lithium aluminium hydride and stirred for30 minutes with elevating the temperature to 50° C. 0.64 g (2.0 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane[Formula (VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N] were added to themixture and stirred at 50° C. for 1 hour.

The reaction solution was poured into 50 ml of ice water and extractedwith ethyl acetate. The separated organic layer was washed withsaturated aqueous saline solution. After dried with anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure toyield 0.72 g of a yellowish oily product.

The resultant oily product was isolated and purified by chromatographyon a column of silica gel to obtain 0.36 g (1.13 mmol) of(+)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol[Formula (I): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N].

Yield: 56.5%.

White crystal, m.p. 137-138° C. (recrystallization from n-hexane/ethylacetate-10/1 ).

[α]_(D) ²⁰ +23.7° (c=10.0, EtOH): 99% ee (by HPLC).

¹ H NMR(CDCl₃); δ 0.60 (s,3H), 1.00 (s,3H), 1.07-1.90 (m,5H), 2.33(bs,2H), 3.53 (s, 1H), 4.13 (s, 2H), 7.06 (d, 2H, J=8 Hz), 7.25 (d, 2H,J=8 Hz), 8.02 (s,1H), 8.25 (s,1H).

IR(KBr, νmax); 3250, 2940, 2850, 1480, 1380, 1262, 1200, 1124, 1080,1002, 840, 800, 720, 670 cm⁻¹.

With the same procedure as preparation example 13, except using thecompound (VI-6) instead of the compound (VI-5),(+)-cis-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)cyclopentanolcan be prepared.

Preparation Example 14

Optically active (+)-oxabicyclohexanemethanol derivative [Formula(IV):R¹ =R² =CH₃, (R)_(n) =4-Cl]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexanemethanol:

15 ml of dichloromethane were placed in a 3-neck flask (50 ml) andstirred at -40° C. (dry ice/acetone) under a nitrogen stream. After 200mg of Molecular Sieve 4A (powdered, activated molecular sieves; AldrichCo.) with stirring, 28.4 mg (0.1 mmol; 5 mol %) of Ti(O i-Pr)₄, 31 mg(0.15 mmol; 7.5 mol %) of (+)-DET and 500 mg (2.0 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] were added thereto and theresultant mixture was stirred at -40° C. for 10 minutes. Thereafter 2.4ml (4.0 mmol) of a toluene solution of anhydrous TBHP (1.67 mol/l) wereadded dropwise so as not to elevate the temperature to -40° C.

After allowed to react at -40° C. for 5 hours, 20 ml of water were addedthereto, followed by stirring for 30 minutes. Thereafter, 5 ml of 30%sodium hydroxide-saturated aqueous common salt liquor were added to themixture, followed by stirring further 30 minutes. After allowed to standfor a while by adding 1 ml of methanol, the formed organic layer wasseparated. The aqueous layer was extracted with dichloromethane. Theseparated organic layers were combined, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 0.63 g of acolorless transparent oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 0.46 g (1.7 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 81%.

Colorless transparent oil.

[α]_(D) ²⁰ +18° (c=1.5, EtOH): 64% ee (by HPLC).

¹ H NMR(CDCl₃); δ 0.9 (s,3H), 1.10 (s,3H), 1.0˜1.83 (m,4H), 2.43 (s,1H),3.0 (s,2H), 3.8 (d, 1H, J=12 Hz), 4.1 (d, 1H, J=12 Hz), 7.13 (m,4H).

IR(neat, νmax); 3400, 2950, 2850, 1482, 1360, 1082, 1010, 836, 780 cm⁻¹.

Preparation Example 15

Optically active (+)-oxabicyclohexanemethanol derivative [Formula (IV):R¹ =R² =CH₃, (R)_(n) =4-Cl]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

5 ml of dichloromethane were placed in a 3-neck flask (50 ml) andstirred at -40° C. (dry ice/acetonitril) under a nitrogen stream. After200 mg of Molecular Sieve 4A (powdered, activated molecular sieves;Aldrich Co.) with stirring, 28.4 mg (0.1 mmol; 10 mol %) of Ti(O i-Pr)₄,32 mg (0.15 mmol; 15 mol %) of (+)-DET and 250 mg (1.0 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] were added thereto and theresultant mixture was stirred at -40° C. for 10 minutes. Thereafter 1.2ml (2.0 mmol) of a toluene solution of anhydrous TBHP (1.67 mol/l) wereadded dropwise so as not to elevate the temperature to -40° C.

After allowed to react at -40° C. for 5 hours, 20 ml of water were addedthereto, followed by stirring for 30 minutes. Thereafter, 5 ml of 30%sodium hydroxide-saturated aqueous saline solution were added to themixture, followed by stirring further 30 minutes. After allowed to standfor a while with adding 1 ml of methanol, the formed organic layer wasseparated. The aqueous layer was extracted with dichloromethane. Theseparated organic layers were combined, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 0.28 g of acolorless transparent oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 0.22 g (1.7 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 82%.

Colorless transparent oil.

[α]_(D) ²⁰ +23.2° (c=1.5, EtOH): 80% ee (by HPLC).

Preparation Example 16

Optically active (+)-oxabicyclohexanemethanol derivative [Formula (IV):R¹ =R² =CH₃, (R)_(n) =4-Cl]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

5 ml of dichloromethane were placed in a 3-neck flask (50 ml) andstirred at -20° C. (dry ice/carbon tetrachloride) under a nitrogenstream. After 200 mg of Molecular Sieve 4A (powdered, activatedmolecular sieves; Aldrich Co.) with stirring, 28.4 mg (0.1 mmol; 10 mol%) of Ti(O i-Pr)₄, 33.7 mg (0.16 mmol; 16 mol %) of (+)-DET and 250 mg(1.0 mmol) of2-[(4-chlorophenyl)-methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] were added thereto and theresultant mixture was stirred at -20° C. for 10 minutes. Thereafter 1.2ml (2.0 mmol) of a toluene solution of anhydrous TBHP (1.67 mol/l) wereadded dropwise so as not to elevate the temperature to -20° C.

After allowed to react at -20° C. for 2 hours, 20 ml of water were addedthereto, followed by stirring for 30 minutes. Thereafter, 5 ml of 30%sodium hydroxide-saturated aqueous saline solution were added to themixture, followed by stirring further 30 minutes. After allowed to standfor a while with adding 1 ml of methanol, the formed organic layer wasseparated. The aqueous layer was extracted with dichloromethane. Theseparated organic layers were combined, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 0.32 g of acolorless transparent oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 206.4 mg (0.77 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 77%.

Colorless transparent oil.

[α]_(D) ²⁰ +12.6° (c=1.2, EtOH): 48% ee (by HPLC).

Preparation Example 17

Optically active (+)-oxabicyclohexanemethanol derivative [Formula (IV):R¹ =R² =CH₃, (R)_(n) =4-Cl]

Preparation of (+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

5 ml of dichloromethane were placed in a 3-neck flask (50 ml) andstirred at 0° C. under a nitrogen stream. After 200 mg of MolecularSieve 4A (powdered, activated molecular sieves; Aldrich Co.) withstirring, 28.4 mg (0.1 mmol; 10 mol %) of Ti(O i-Pr)₄, 32 mg (0.15 mmol;15 mol %) of (+)-DET and 250 mg (1.0 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =CH₃, (R)_(n) =4-Cl] were added thereto and theresultant mixture was stirred at 0° C. for 10 minutes. Thereafter 1.2 ml(2.0 mmol) of a toluene solution of anhydrous TBHP (1.67 mol/l) wereadded dropwise so as not to elevate the temperature to 0° C.

The reaction was completed in 30 minutes. After 20 ml of water wereadded and stirred at room temperature for 30 minutes, 5 ml of 30% sodiumhydroxide-saturated aqueous saline solution were added to the mixture,followed by stirring further 30 minutes. After allowed to stand for awhile with adding 1 ml of methanol, the resulted organic layer wasseparated. The aqueous layer was extracted with dichloromethane. Theseparated organic layers were combined, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 0.28 g of acolorless transparent oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 196.4 mg (0.74 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 74%.

Colorless transparent oil.

[α]_(D) ²⁰ +7° (c=1.5, EtOH): 20 % ee (by HPLC).

Preparation Example 18

Optically active (+)-oxabicyclohexanemethanol derivative [Formula (IV):R¹ =R² =CH₃, (R)_(n) =4-Cl]

Preparation of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol:

5 ml of dichloromethane were placed in a 3-neck flask (50 ml) andstirred at -40° C. (dry ice/acetonitril) under a nitrogen stream. After200 mg of Molecular Sieve 4A (powdered,. activated molecular sieves;Aldrich Co.) with stirring, 29.8 mg (0.105 mmol; 7 mol %) of Ti(Oi-Pr)₄, 33 mg (0.15 mmol; 10 mol %) of (+)-DET and 376 mg (1.5 mmol) of2-[(4-chlorophenyl)methyl]-5,5-dimethyl-1-cyclopentene-1-methanol[Formula (III): R¹ =R² =C₃, (R)_(n) =4-Cl] were added thereto and theresultant mixture was stirred at -40° C. for 10 minutes. Thereafter 1.2ml (2.0 mmol) of a toluene solution of anhydrous TBHP (1.67 mol/l) wereadded dropwise so as not to elevate the temperature to -40° C.

After allowed to react at -40° C. for 5 hours, 20 ml of water were addedthereto, followed by stirring for 30 minutes. Thereafter, 5 ml of 30%sodium hydroxide-saturated aqueous saline solution were added to themixture, followed by stirring further 30 minutes. After allowed to standPot a while with adding 1 ml of methanol, the resulted organic layer wasseparated. The aqueous layer was extracted with dichloromethane. Theseparated organic layers were combined, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 0.45 g of acolorless transparent oily product.

The resultant product was purified by chromatography on a column ofsilica gel to obtain 330.6 mg (1.24 mmol) of(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-6-oxabicyclo[3.1.0]hexane-1-methanol[Formula (IV): R¹ =R² =CH₃, (R)_(n) =4-Cl].

Yield: 82.7%.

Colorless transparent oil.

[α]_(D) ²⁰ +23.5° (c=1.5, EtOH): 72% ee (by HPLC).

    ______________________________________                                        Formulation Example 1: Dust                                                                Parts by weight                                                  ______________________________________                                        Compound (VI)   3                                                             Clay           40                                                             Talc           57                                                             ______________________________________                                    

The above-mentioned ingredients were mixed to prepare a dust.

    ______________________________________                                        Formulation Example 2: Wettable powder                                                      Parts by weight                                                 ______________________________________                                        Compound (VI)   50                                                            Ligninsulfonate  5                                                            Alkylsulfonate   3                                                            Diatomaceous earth                                                                            42                                                            ______________________________________                                    

The above-mentioned ingredients were mixed to prepare a wettable powder.

    ______________________________________                                        Formulation Example 3: Granule                                                             Parts by weight                                                  ______________________________________                                        Compound (VI)   5                                                             Bentonite      43                                                             Clay           45                                                             Ligninsulfonate                                                                               7                                                             ______________________________________                                    

The above-mentioned ingredients were mixed and kneaded with adding waterthereto. The mixture was gnalurated by means of an extrusion granulatingmachine, followed by drying to obtain granules.

    ______________________________________                                        Formulation Example 4: Emulsion                                                                    Parts by weight                                          ______________________________________                                        Compound (VI)          20                                                     Polyoxyethylene alkyl aryl ether                                                                     10                                                     Polyoxyethylnene sorbitan monolaurate                                                                 3                                                     Xylene                 67                                                     ______________________________________                                    

The above mentioned ingredients were mixed and dissolved to obtain anemulsion.

TEST EXAMPLE Antimicrobial Test Against Various Microorganisms

This example shows results of the following antimicrobial test ofoptically active (-)-azolylmethyloxabicyclohexane derivative (formula(VI): R¹ =R² =CH₃, (R)_(n) =4-Cl, A=N) prepared in Preparation Example 8against various kinds of plant disease microorganisms.

Method

The compound of this invention was dissolved in dimethylsulfoxide in asuitable concentration. 0.6 ml of the solution was well mixed with 60 mlof a PAS culture medium at about 60° C. in a 100 ml conical flask, andthe resultant mixture was poured into Petri dishes and was caused tocoagulate, by which plate culture media containing the compound of thisinvention were obtained.

On the other hand, plate culture media on which test microorganisms werepreviously cultured were punched by a cork borer so as to have adiameter of 4 mm, followed by inoculating on the above-mentioned plateculture medium. After inoculation was carried out, they were incubatedfor 1-3 days at a preferable temperature for each microorganism, andgrowth of microorganisms was obserbed by measuring the diameter of thecolony. Hyphae elongation inhibitory rates were determined respectivelyin accordance with the below-described equation.

    R=100 (dc-dt)/dc

wherein R=Hyphae elongation inhibitory rate (%) dc=Diameter of colony onthe non-treated plate culture medium dt=Diameter of colony on the plateculture medium containing the tested compound.

Test results were ranked in five stages by the following ranking system.The results are shown in Table 1.

    ______________________________________                                               5   at least 90%-100%                                                         4   at least 70% but lower than 90%                                           3   at least 40% but lower than 70%                                           2   at least 20% but lower than 40%                                           1   lower than 20%                                                     ______________________________________                                    

                  TABLE 1                                                         ______________________________________                                                             Biocidal activity                                                             (concentration:                                          Test fungus          100 μg/ml)                                            ______________________________________                                        Pyricularia oryzae   5                                                        Cochliobolus miyabeanus                                                                            5                                                        Gibberella fujikuroi 5                                                        Helminthosporium sigmoideum                                                                        5                                                        Rhizoctonia solani   3                                                        Botrytis cinerea     5                                                        Sclerotinia sclerotiorum                                                                           5                                                        Fusarium oxysporum f. sp. niveum                                                                   5                                                        Fusarium oxysporum f. sp.                                                                          5                                                        cucumerinum                                                                   Fusarium oxysporum f. sp. raphani                                                                  5                                                        Colletotrichum lagenarium                                                                          4                                                        Cercospola beticola  5                                                        Cercospore kikuchii  4                                                        Monilinia fructicola 5                                                        Alternaria kikuchiana                                                                              4                                                        Alternaria mali      5                                                        Glomerella cingulate 5                                                        ______________________________________                                    

We claim:
 1. An azolymethyloxabicyclohexane derivative represented bythe formula (VI) ##STR24## wherein R¹ and R² denote each a hydrogen atomor a C₁ -C₅ alkyl group, R denotes a halogen atom, a nitro group, acyano group, a C₁ -C₅ alkyl group, a C₁ -C₅ haloalkyl group or a phenylgroup, A denotes a methine group, and n stands for 0 or an integer of1-5.
 2. The azolylmethyloxabicyclohexane derivative of claim 1, whereinR¹ is CH₃, R² is CH₃, R is 4-Cl and n is
 1. 3. Theazolylmethyloxabicyclohexane derivative of claim 1 which is(+)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane.4. The azolylmethyloxabicyclohexane derivative of claim 1 which is(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane.5. A fungicidal composition comprising an effective amount of anazolylmethyloxabicyclohexane derivative represented by the formula (VI),as an active ingredient, together with an inert carrier or otheradjuvants ##STR25## wherein R¹, R², R, A and n have the same meanings asdefined in claim
 1. 6. The fungicidal composition of claim 5, wherein R¹is CH₃, R² is CH₃, R is 4-Cl, and n is
 1. 7. The fungicidal compositionof claim 5, wherein the azolylmethyloxabicyclohexane derivative is(-)-5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-imidazol-1-ylmethyl)-6-oxabicyclo[3.1.0]hexane.